Aryl alkanoic acid phloroglucinol ester compound as well as preparation method and application thereof

Abstract

The invention discloses a tris (aryl alkanoic acid) phloroglucinol ester compound, a preparation method and an effect of the tris (aryl alkanoic acid) phloroglucinol ester compound in analgesia. According to the invention, aryl alkyl acid antipyretic and analgesic drugs and phloroglucinol are combined to obtain a novel tris (aryl alkyl acid) phloroglucinol ester compound with good analgesic effect, long action time and small blood concentration fluctuation, and the range of existing spasmolysis and analgesic drugs is widened. The traditional Chinese medicine composition has good spasmolysis and analgesia effects, and meets the requirements of the field of medicines.

Description

Technical Field

[0001] The present invention relates to a class of tri(arylalkanoic acid)phloroglucinol esters, a manufacturing method thereof, and uses thereof. Specifically, it relates to a class of tri(arylalkanoic acid)phloroglucinol esters having a long-acting analgesic effect. Background Art

[0002] Non-steroidal anti-inflammatory drugs (NSAIDs) are a widely used class of drugs that can relieve various moderate pains. Especially in daily life, arylalkanoic acid non-steroidal anti-inflammatory drugs are often taken orally to relieve dysmenorrhea (Zahradnik H, et al. Contraception, 2010, 81(3): 185-96.). The analgesic mechanism of this class of drugs is to inhibit the activity of cyclooxygenase (COX), thereby inhibiting the metabolism of arachidonic acid to reduce the content of prostaglandin (PG) (Hayes E, et al. Obstetrical & gynecological survey, 2002, 57(11): 768-80.). However, long-term use has a stimulating effect on the gastrointestinal tract, and in severe cases, it may even cause gastric ulcers and gastric bleeding (Markenson J A. Pain Symptom Manage, 2002, 24(1 Suppl): S10-S7.). Drugs such as aspirin and ibuprofen on the market are made into enteric-coated preparations to avoid the gastrointestinal stimulating effect.

[0003] The smooth muscle analgesic drug phloroglucinol. It is mainly used to relieve acute spastic pain of the gastrointestinal tract, severe vomiting, and gynecological spastic pain (Clara B, et al. European journal of clinical pharmacology, 2020, 76(1): 1-6.). There are clinical studies showing that phloroglucinol can also relieve primary dysmenorrhea by relieving the spasm of uterine smooth muscle (Yin Rong, et al. Evaluation and analysis of drug use in Chinese hospitals, 2020, 20(06): 695-7.). Its effect is safer and more effective. However, at present, the administration route of phloroglucinol in clinical practice in China is single, mostly by injection. If taken orally, it will be decomposed by gastric acid, reducing its bioavailability. The gastrointestinal irritation of arylalkanoic acid antipyretics and analgesics and the chemical properties of phloroglucinol limit their applications.

[0004] Therefore, in the present invention, the phenolic hydroxyl group of phloroglucinol is esterified with the carboxyl group of arylalkanoic acid antipyretics and analgesics, which can reduce the irritation of the carboxyl group to the gastrointestinal tract and also increase the oral bioavailability of phloroglucinol. Summary of the Invention

[0005] The present invention discloses a compound formed by esterifying the hydroxyl group of phloroglucinol with an antipyretic and analgesic agent of arylalkanoic acid type, so as to solve the drawbacks of intestinal irritation of the antipyretic and analgesic agent of arylalkanoic acid type and low oral bioavailability of phloroglucinol.

[0006] Another technical problem to be solved by the present invention is to disclose a preparation method of the compound.

[0007] Another technical problem to be solved by the present invention is to disclose the application of the compound in analgesic drugs to meet the needs of the medical field.

[0008] The technical concept of the present invention is as follows:

[0009] The inventor combines an antipyretic and analgesic agent of arylalkanoic acid type with phloroglucinol to obtain a class of new tris(arylalkanoic acid)phloroglucinol ester compounds with good oral bioavailability and long-acting analgesic effect.

[0010] The tris(arylalkanoic acid)phloroglucinol ester compounds of the present invention are compounds having the following general structural formula:

[0011]

[0012] Wherein R is an antipyretic and analgesic agent of arylalkanoic acid type, including acetylsalicylic acid, ibuprofen, flurbiprofen, ketoprofen, naproxen, indoprofen, fenoprofen, pirprofen, suprofen, tiaprofenic acid, indomethacin, sulindac, zidometacin, tolmetin, diclofenac, etodolac, fenbufen, etc.

[0013] The preferred compounds of the present invention include but are not limited to:

[0014] Benzene-1,3,5-triyl tris(2-acetoxybenzoate) (Code No. 101);

[0015] Benzene-1,3,5-triyl tris(2-(4-isobutylphenyl)propionate) (Code No. 102);

[0016] Benzene-1,3,5-triyl tris(2-(4-benzoylphenyl)propionate) (Code No. 103);

[0017] Benzene-1,3,5-triyl tris(2-(2-fluoro-[1,1'-biphenyl]-4-yl)propionate) (Code No. 104);

[0018] Benzene-1,3,5-triyl tris(2-(6-methoxynaphthalen-2-yl)propionate) (Code No. 105);

[0019] Benzene-1,3,5-triyl tris(2-(1-(4-chlorobenzoyl)-5-methoxy-2-methyl-1H-indol-3-yl)acetate) (Code No. 106).

[0020] The preparation method of the tris(arylalkanoic acid) phloroglucinol ester compounds of the present invention comprises the following steps:

[0021] The compound with the general formula (1) is obtained by using an arylalkanoic acid antipyretic analgesic as a raw material, reacting with a chlorinating reagent to obtain an arylalkanoyl chloride, and then condensing with phloroglucinol.

[0022] The compound with the general formula (1) can also be obtained by using an arylalkanoic acid antipyretic analgesic as a raw material, activating it with a condensing agent and then condensing with phloroglucinol.

[0023] Specifically, the synthesis of the compound with the general formula (1) is carried out as follows: The arylalkanoic acid antipyretic analgesic reacts with a chlorinating reagent and a catalyst in a solvent to generate an arylalkanoyl chloride.

[0024] The reaction temperature is -5 to 80 °C, and the reaction time is 0.5 to 5 h; the said solvent is one or a mixture of dichloromethane, tetrahydrofuran, and acetone; the said chlorinating reagent is one or a mixture of thionyl chloride, phosphorus trichloride, phosphorus pentachloride, phosphorus oxychloride, or oxalyl chloride; the said catalyst is N,N-dimethylformamide.

[0025] The arylalkanoyl chloride and phloroglucinol react in a solvent under the action of an acid-binding agent to generate the compound with the general formula (1); 4) The reaction temperature is -5 to 40 °C, and the reaction time is 1 to 5 h; the said solvent is one or a mixture of ethyl acetate, dichloromethane, acetone, and tetrahydrofuran; the said acid-binding agent is Na 2 CO 3 、K 2 CO 3 、KOH, NaOH, triethylamine, or N,N-diisopropylethylamine, or a mixture of one or more of them.

[0026] The synthesis of the compound with the general formula (1) can also be carried out as follows: The arylalkanoic acid antipyretic analgesic is activated with a condensing agent in a solvent and then reacts with phloroglucinol in a solvent to generate the compound with the general formula (1).

[0027] The reaction temperature is 0 to 40 °C, and the reaction time is 1 to 24 h; one or a mixture of ethyl acetate, dichloromethane, acetone, acetonitrile, N,N-dimethylformamide (DMF), and dimethyl sulfoxide; the said condensing agent is one or a mixture of DCC, EDCI, HOBT, HATU, and HBTU.

[0028] In vivo and in vitro analgesic experiments are carried out on the tris(arylalkanoic acid) phloroglucinol ester compounds of the present invention.

[0029] The acetic acid-induced writhing test in mice and the primary dysmenorrhea test in mice were used to detect Compound 102. Compared with ibuprofen and phloroglucinol, Compound 102 could effectively prolong the writhing latency and reduce the number of writhing in mice. The oxytocin-induced isolated uterine contraction activity test in mice was used to detect Compound 102. The effect of Compound 102 on the contraction amplitude of isolated mouse uterus was roughly equivalent to that of phloroglucinol. The pharmacokinetic experiment in rats showed that after intragastric administration, compared with ibuprofen, Compound 102 could slowly and steadily release the metabolite ibuprofen through metabolism, achieving a longer half-life and avoiding drastic fluctuations in blood drug concentration.

[0030] As can be seen from the above-disclosed technical solutions, the compound of the present invention has excellent analgesic effects, and the preparation method is easy, convenient for industrial production, and can meet the needs of the pharmaceutical field. The present invention has the advantages of good analgesic effect, long action time, and small fluctuations in blood drug concentration. Detailed implementation mode

[0031] Example 1 Synthesis of benzene-1,3,5-triyl tris(2-acetoxybenzoate) (Code 101)

[0032] Dissolve acetylsalicylic acid (5.94 g, 33 mmol) in dichloromethane, add one drop of DMF, and dropwise add thionyl chloride (2.9 mL, 40 mmol). React at 40 °C for 1 h, monitor the reaction process by TLC, and evaporate the solvent after the reaction is completed to obtain acetylsalicyloyl chloride. Dissolve phloroglucinol (1.26 g, 10 mmol) in ethyl acetate, add triethylamine (5.6 mL, 40 mmol), and dissolve acetylsalicyloyl chloride in ethyl acetate. Dropwise add it into the phloroglucinol solution under ice bath conditions and react for 1 h. After the reaction is completed, wash with 10% aqueous sodium carbonate solution, then wash with pure water until neutral, dry with anhydrous sodium sulfate, and evaporate the solvent to obtain an oily liquid. Add a small amount of absolute ethanol and place it at -20 °C for 24 h to precipitate a white solid. Nuclear magnetic resonance hydrogen spectrum 1 H NMR (500 MHz, DMSO) δ 8.20 (d, J = 7.7 Hz, 3H), 7.80 (t, J = 7.7 Hz, 3H), 7.52 (t, J = 7.6 Hz, 3H), 7.35 (d, J = 8.1 Hz, 3H), 7.27 (s, 3H), 2.28 (s, 9H).

[0033] Example 2 Synthesis of benzene-1,3,5-triyl tris(2-(4-isobutylphenyl)propionate) (Code 102)

[0034] Use 2-(4-isobutylphenyl)propionic acid instead of 2-acetoxybenzoic acid and prepare benzene-1,3,5-triyl tris(2-(4-isobutylphenyl)propionate) according to the method of Example 1, with a yield of 90.5%

[0035] Nuclear magnetic resonance hydrogen spectrum1 1H NMR (500 MHz, DMSO) δ 7.26 (d, J = 7.8 Hz, 6H), 7.14 (d, J = 7.9 Hz, 6H), 6.72 (s, 3H), 4.01 (q, J = 7.0 Hz, 3H), 2.43 (d, J = 7.1 Hz, 6H), 1.87–1.77 (m, 3H), 1.47 (d, J = 7.1 Hz, 9H), 0.86 (d, J = 6.6 Hz, 18H).

[0036] Synthesis of Example 3: Phenyl-1,3,5-tris(2-(4-benzoylphenyl)propionate) (Code No. 103)

[0037] Using 2-(4-benzoylphenyl)propionic acid instead of 2-acetoxybenzoic acid, phenyl-1,3,5-tris(2-(4-benzoylphenyl)propionate) was prepared according to the method of Example 1, with a yield of 92.3%.

[0038] 1H Nuclear Magnetic Resonance Spectrum 1 1H NMR (500 MHz, DMSO) δ 7.77–7.49 (m, 27H), 6.87 (s, 3H), 4.24 (q, J = 7.1 Hz, 3H), 1.54 (d, J = 7.1 Hz, 9H).

[0039] Synthesis of Example 4: Phenyl-1,3,5-tris(2-(2-fluoro-[1,1'-biphenyl]-4-yl)propionate) (Code No. 104)

[0040] Using 2-(2-fluoro-[1,1'-biphenyl]-4-yl)propionic acid instead of 2-acetoxybenzoic acid, phenyl-1,3,5-tris(2-(2-fluoro-[1,1'-biphenyl]-4-yl)propionate) was prepared according to the method of Example 1, with a yield of 86.7%.

[0041] 1H Nuclear Magnetic Resonance Spectrum 1 1H NMR (500 MHz, DMSO) δ 7.58–7.32 (m, 24H), 6.94 (s, 3H), 4.18 (q, J = 7.1 Hz, 3H), 1.56 (d, J = 7.1 Hz, 9H).

[0042] Synthesis of Example 5: Phenyl-1,3,5-tris(2-(6-methoxynaphthalen-2-yl)propionate) (Code No. 105)

[0043] Using 2-(6-methoxynaphthalen-2-yl)propionic acid instead of 2-acetoxybenzoic acid, phenyl-1,3,5-tris(2-(6-methoxynaphthalen-2-yl)propionate) was prepared according to the method of Example 1, with a yield of 89.3%.

[0044] 1H Nuclear Magnetic Resonance Spectrum 1 1H NMR (500 MHz, DMSO) δ 7.85–7.78 (m, 9H), 7.46 (d, J = 8.7 Hz, 3H), 7.31 (d, J = 1.8 Hz, 3H), 7.17 (dd, J = 8.9, 2.3 Hz, 3H), 6.77 (s, 3H), 4.16 (zq, J = 6.9 Hz, 3H), 3.88 (s, 9H), 1.56 (d, J = 7.0 Hz, 9H).

[0045] Synthesis of Example 6: Phenyl-1,3,5-tris(2-(1-(4-chlorobenzoyl)-5-methoxy-2-methyl-1H-indol-3-yl)acetate) (Code Name 106)

[0046] Using 2-(1-(4-chlorobenzoyl)-5-methoxy-2-methyl-1H-indol-3-yl)acetic acid instead of 2-acetoxybenzoic acid, phenyl-1,3,5-tris(2-(1-(4-chlorobenzoyl)-5-methoxy-2-methyl-1H-indol-3-yl)acetate) was prepared according to the method of Example 1, with a yield of 88.4%.

[0047] 1H Nuclear Magnetic Resonance Spectrum 1 1H NMR (500 MHz, DMSO) δ 7.68 (d, J = 8.5 Hz, 6H), 7.63 (d, J = 8.6 Hz, 6H), 7.15 (d, J = 2.4 Hz, 3H), 6.98 (s, 3H), 6.95 (d, J = 9.0 Hz, 3H), 6.73 (dd, J = 9.0, 2.4 Hz, 3H), 4.07 (s, 6H), 3.74 (s, 9H), 2.26 (s, 9H).

[0048] Example 7: Mouse Acetic Acid Writhing Test

[0049] The specific method is as follows, and the results are shown in Table 1.

[0050] (1) Grouping: After 7 days of adaptive feeding, the mice were randomly divided into a model group (equal volume of normal saline), an ibuprofen group (0.16 g / kg), a low-dose group (0.16 g / kg), a medium-dose group (0.48 g / kg), and a high-dose group (1.44 g / kg) of Compound 102.

[0051] (2) Administration and Modeling: Continuous intragastric administration was carried out for 5 days according to the grouping, once a day. 30 minutes after the last administration, each mouse was intraperitoneally injected with 0.6% acetic acid (0.2 mL / mouse). After injection, the writhing latency and the number of writhing of the mice were observed and recorded within 20 minutes. (Note that the acetic acid should be prepared freshly and thermostatically water-bathed to 37 °C before injection).

[0052] Effect of Compound 102 on acetic acid-induced writhing in mice (Mean±SEM, n = 8)

[0053]

[0054] Compared with the model group, * P < 0.05, ** P < 0.01, *** P < 0.001

[0055] Experiment on primary dysmenorrhea in mice in Implementation Case 8

[0056] The specific method is as follows, and the results are shown in Table 2

[0057] (1) Pre-screening of mice: Kunming mice were adaptively fed for one week, fasted but not water-deprived one day before the experiment; weighed, randomly caged, and numbered.

[0058] Intraperitoneal injection of estradiol benzoate (10 mg / kg) was performed continuously for 9 days. Fasted but not water-deprived on the ninth night, after weighing on the tenth day, oxytocin (50 U / kg) was intraperitoneally injected, and the number of writhing times within 30 min was observed.

[0059] (2) Grouping: After 5 days of recovery, mice with writhing times greater than 5 were selected. Divided into six groups: model group (equal volume of normal saline), phloroglucinol group (0.02 g / kg), ibuprofen group (0.16 g / kg), low-dose compound 102 group (0.16 g / kg), medium-dose group (0.48 g / kg), high-dose group (1.44 g / kg).

[0060] (3) Drug administration and modeling: Each group was intraperitoneally injected with estradiol benzoate (10 mg / kg) continuously for 6 days. On the 7th day, drugs were administered once according to the grouping. Two hours after drug administration, oxytocin (50 U / kg) was intraperitoneally injected, and the writhing latency and the number of writhing times of each group of mice within 30 min were observed.

[0061] Table 2 Effect of Compound 102 on the writhing response of mice in the primary dysmenorrhea model (Mean±SEM, n = 6)

[0062]

[0063] Compared with the model group, * P < 0.05, ** P < 0.01, *** P < 0.001; compared with the phloroglucinol group, # P < 0.05

[0064] Experiment on isolated uterine muscle strips of mice in Implementation Case 9

[0065] The specific method is as follows, and the results are shown in Table 3 and Table 4.

[0066] (1) Preparation of isolated uterine muscle strips from mice

[0067] Take healthy female Kunming mice, weigh them, and number them. Inject estradiol benzoate (10 mg / kg) intraperitoneally for 3 consecutive days to make the mice in estrus and increase the sensitivity of the uterus to oxytocin. Fast the mice overnight on the third day without restricting water intake. Anesthetize the mice with 10% urethane (0.14 mL / 20 g) on the fourth day, quickly remove the uterus and wash it in Locke's solution. Carefully strip away other fats and connective tissues around the isolated uterus, and then cut it into uterine muscle strips about 1 cm long (take the middle segment of uterine smooth muscle).

[0068] (2) Effect of compound 102 on oxytocin-induced contraction of isolated uterine muscle strips from mice

[0069] Fixation of muscle strips: Fix one end of the muscle strip to a glass cylinder containing 18 mL of Locke's solution with a silk thread, and connect the other end to a tension transducer with a silk thread.

[0070] Condition setting and equilibration: The temperature of Locke's solution is controlled by a constant temperature water bath at about 37 °C, and continuous oxygen supply (95% oxygen + 5% carbon dioxide) is provided. Detect the contraction of the isolated uterine muscle strips through a biological function experimental system, adjust the transducer to add a load of 1 g, and start the experiment after the spontaneous contraction of the uterus is stable for at least 30 min.

[0071] Model establishment and drug administration: Record the situation of the spontaneous contraction curve of the uterus for 10 min. Then add 9 μL of oxytocin (final concentration 5 μL / L) to replicate the contraction model of isolated uterine smooth muscle, react for 10 min and record its contraction situation. Add 20 μL of Locke's solution (solvent control group), phloroglucinol (final concentration 0.1 mM), ibuprofen (final concentration 0.2 mM), and compound 102 (final concentration 0.1 mM) to the bath according to the grouping, observe and record the contraction curve situation for 10 min after drug administration, and analyze the uterine contraction amplitude and average uterine contraction tension in each group before and after drug administration.

[0072] Table 3 Changes in the contraction amplitude of isolated uterine smooth muscle in mice (Mean±SEM, n = 6)

[0073]

[0074] Compared with before model establishment, * P < 0.05, ** P < 0.01; compared with after model establishment, # P < 0.05

[0075] Table 4 Changes in the average contraction tension of isolated uterine smooth muscle in mice (Mean±SEM, n = 6)

[0076]

[0077] Compared with before modeling, * P < 0.05, ** P < 0.01, *** P < 0.01; compared with after modeling, # P < 0.05, ## P < 0.01

[0078] Pharmacokinetics experiment of compound 102 in 10 rats

[0079] The specific method is as follows, and the results are shown in Table 5.

[0080] (1) Administration regimen and blood sample collection

[0081] Weigh and number the rats, and divide them into three groups: compound 102 (0.800 g / kg, 1.600 g / kg) and ibuprofen (0.159 g / kg). Administration regimen: Female SD rats were adaptively fed for 5 days. Fast the rats overnight (without water restriction) one day before the gavage administration experiment. Blood sample collection: Collect blood at 2, 12, 18, 20, 22, 24, 28, 36, 48 h after administration (compound 102 group); collect blood at 0.083, 0.25, 0.5, 1, 2, 6, 8, 12, 24, 36 h after administration (ibuprofen group). Collect blood from the orbital venous plexus into a pre-heparinized 1.5 mL centrifuge tube with a heparinized capillary, centrifuge at 9000 rpm for 10 min (4 °C), take the supernatant, and store it at -20 °C for later use.

[0082] (2) Preparation of standard solutions

[0083] Accurately weigh 0.0100 g of compound 102 and ibuprofen reference substances, add an appropriate amount of acetonitrile, vortex and ultrasonically dissolve to prepare a stock solution with a concentration of 10.00 mg / mL, and store it in a refrigerator at 4 °C. Dilute it with acetonitrile to a series of concentration standard solutions of compound 102 and ibuprofen when in use.

[0084] Accurately weigh 0.0100 g of flurbiprofen reference substance, add an appropriate amount of acetonitrile and ultrasonically dissolve to prepare a flurbiprofen stock solution (internal standard) with a concentration of 10.00 mg / mL, and store it refrigerated at 4 °C for later use; dilute it with acetonitrile to a 100 μg / mL flurbiprofen solution as the working internal standard solution when in use.

[0085] (3) Treatment of plasma samples

[0086] Treatment of plasma samples: Take 100 μL of plasma sample and add it to a 1.5 mL centrifuge tube. Add 25 μL of internal standard solution (100 μg / mL flurbiprofen), then add 125 μL of acetonitrile. Vortex for 5 min, centrifuge at 9000 rpm for 10 min (at 4 °C), and take the supernatant to a 1.5 mL centrifuge tube. Then centrifuge at 14000 rpm for 10 min (at 4 °C), take the supernatant into a sample vial, and inject 20 μL for determination.

[0087] Table 5 Main pharmacokinetic parameters of compound 102 (metabolite ibuprofen) and ibuprofen after intragastric administration to rats by non-compartmental model

[0088]

Claims

1. A compound of trimesitol esters of tri(arylalkanoic acid), characterized in that, it is a compound having the following general structural formula: wherein R is an arylalkanoic acid antipyretic analgesic, including acetylsalicylic acid, ibuprofen, flurbiprofen, ketoprofen, naproxen, indoprofen, fenoprofen, pirprofen, suprofen, tiaprofenic acid, indomethacin, sulindac, zidometacin, tolmetin, diclofenac, etodolac, fenbufen, etc.

2. The compound according to claim 1, characterized in that, the said compound includes but is not limited to: Benzene-1,3,5-triyl tris(2-acetoxybenzoate) (Code No. 101); Benzene-1,3,5-triyl tris(2-(4-isobutylphenyl)propionate) (Code No. 102); Benzene-1,3,5-triyl tris(2-(4-benzoylphenyl)propionate) (Code No. 103); Benzene-1,3,5-triyl tris(2-(2-fluoro-[1,1'-biphenyl]-4-yl)propionate) (Code No. 104); Benzene-1,3,5-triyl tris(2-(6-methoxynaphthalen-2-yl)propionate) (Code No. 105); Benzene-1,3,5-triyl tris(2-(1-(4-chlorobenzoyl)-5-methoxy-2-methyl-1H-indol-3-yl)acetate) (Code No. 106).

3. The preparation method of the compound according to claim 1 or 2, characterized in that, the compound of general formula (1) comprises the following steps: 1) Reacting an arylalkanoic acid antipyretic analgesic with a chlorinating reagent and a catalyst in a solvent to form an acyl chloride; 2) The reaction temperature is -5 to 80 °C, and the reaction time is 0.5 to 5 h; the said solvent is one or a mixture of dichloromethane, tetrahydrofuran, and acetone; the said chlorinating reagent is one or a mixture of thionyl chloride, phosphorus trichloride, phosphorus pentachloride, phosphorus oxychloride, or oxalyl chloride; the said catalyst is N,N-dimethylformamide. 3) Reacting the arylalkanoyl chloride with phloroglucinol in a solvent under the action of an acid-binding agent to form a compound having general formula (1); 4) The reaction temperature is -5 to 40 °C, and the reaction time is 1 to 5 h; the solvent is one or a mixture of ethyl acetate, dichloromethane, acetone, and tetrahydrofuran; the acid-binding agent is Na 2 CO 3 、K 2 CO 3 、KOH, NaOH, triethylamine or N,N-diisopropylethylamine, or a mixture thereof; 5) Activating the arylalkanoic acid antipyretic analgesic with a condensing agent in a solvent, and reacting with phloroglucinol in a solvent to form a compound of general formula (1); 6) The reaction temperature is 0 to 40 °C, and the reaction time is 1 to 24 h; one or a mixture of ethyl acetate, dichloromethane, acetone, acetonitrile, N,N-dimethylformamide, and dimethyl sulfoxide; the said condensing agent is one or a mixture of DCC, EDCI, HOBT, HATU, or HBTU.

4. A composition containing a therapeutically effective amount of the compound according to claim 1 and a pharmaceutically acceptable carrier.

5. The application of the compound according to claim 1 or 2 as an analgesic drug.

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